Cytokine APRIL protects from atherosclerotic cardiovascular disease


Date:
August 26, 2021
Source:
Medical University of Vienna
Summary:
Heart attacks and strokes are the main causes of death and loss of
productive years globally. These clinical complications are caused
by atherosclerosis, which is a chronic disease that leads to the
accumulation of LDL cholesterol and immune cells in the inner layer
of arteries and thereby resulting in the build-up of atherosclerotic
plaques. Researchers have now identified that a cytokine called
A Proliferation Inducing Ligand (APRIL) plays a major protective
role against the formation of atherosclerotic plaques.



FULL STORY ========================================================================== Heart attacks and strokes are the main causes of death and loss of
productive years globally. These clinical complications are caused by atherosclerosis, which is a chronic disease that leads to the accumulation
of LDL cholesterol and immune cells in the inner layer of arteries and
thereby resulting in the build-up of atherosclerotic plaques. Researchers
from the Department of Laboratory Medicine of the Medical University of
Vienna in collaboration with colleagues from the University of Lausanne (Switzerland) and the University of Cambridge (UK) have identified that
a cytokine called A Proliferation Inducing Ligand (APRIL) plays a major protective role against the formation of atherosclerotic plaques. The
study was now published in the journal Nature.


==========================================================================
The investigators found that genetically engineered mice that do not
express APRIL developed more atherosclerosis. They further confirmed
this discovery by injecting mice with neutralizing antibodies against
APRIL, which also lead to the development of bigger atherosclerotic
plaques. APRIL binds immune receptors that are predominately expressed
by B lymphocytes and thereby regulates antibody production and the
survival of antibody-producing cells. Because of these properties, APRIL
is being explored as a therapeutic target in autoimmune diseases. "We
initially hypothesized that the protective properties of APRIL against atherosclerotic plaque formation are mediated via its ability to regulate
B lymphocyte responses that play a crucial role in atherosclerosis.

However, this hypothesis was wrong. We then focused on an unappreciated
non- immunological property of APRIL that is its ability to bind to proteoglycans," says Dimitrios Tsiantoulas, Research group leader at the Department of Laboratory Medicine of the Medical University of Vienna
and lead author of the study.

The authors demonstrated that APRIL is produced in high amounts directly
inside the arteries where it binds to the proteoglycan Perlecan
(or heparan sulfate proteoglycan 2), which is a large molecule that
decorates the inner layer of arteries. The investigators showed that administration of neutralizing antibodies against APRIL in mice that
express a genetically engineered form of Perlecan, which APRIL cannot
bind, had no effect on atherosclerotic plaque development. "These data
clearly show that the protective properties of APRIL in atherosclerosis
are mediated by its ability to bind to proteoglycans in arteries" says Christoph Binder, Professor of Atherosclerosis Research at the Department
of Laboratory Medicine of the Medical University of Vienna and senior
author of the study. Perlecan has previously been shown to promote the retention of LDL cholesterol, which according to the present study can
be mitigated by APRIL. Furthermore, the authors identified a specific anti-APRIL antibody that enhances the binding of APRIL to proteoglycans
and reduced atherosclerosis in mice. "The development of therapeutics
that increase the binding of APRIL to proteoglycans could be a new line
of treatment for atherosclerotic disease" says Dimitrios Tsiantoulas.

Furthermore, the authors investigated the relevance of APRIL in
atherosclerotic disease in humans. Using several tools, which were
developed by Pascal Schneider, Senior Researcher at the University of
Lausanne and co-author of the study, the investigators discovered that
human blood contains an additional and previously unknown form of APRIL
that they named non-canonical APRIL (nc- APRIL). In contrast to the known
form of APRIL, which they call now canonical APRIL (c-APRIL), nc-APRIL
binds only proteoglycans and does not bind to immune receptors. "By
analysing blood samples from more than 3,000 patients we found that
levels of nc-APRIL in the blood predict risk of death from cardiovascular disease, which provides evidence that the interaction of APRIL and proteoglycans may play a role atherosclerotic disease in humans" says
Christoph Binder.

========================================================================== Story Source: Materials provided by Medical_University_of_Vienna. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Dimitrios Tsiantoulas, Mahya Eslami, Georg Obermayer, Marc Clement,
Diede
Smeets, Florian J. Mayer, Ma'te' G. Kiss, Lennart Enders, Juliane
Weisser, Laura Go"derle, Jordi Lambert, Florian Frommlet, Andre'
Mueller, Tim Hendrikx, Maria Ozsvar-Kozma, Florentina Porsch,
Laure Willen, Taras Afonyushkin, Jane E. Murphy, Per Fogelstrand,
Olivier Donze', Gerard Pasterkamp, Matthias Hoke, Stefan Kubicek,
Helle F. Jo/rgensen, Nicolas Danchin, Tabassome Simon, Hubert
Scharnagl, Winfried Ma"rz, Jan Bore'n, Henry Hess, Ziad Mallat,
Pascal Schneider, Christoph J. Binder. APRIL limits atherosclerosis
by binding to heparan sulfate proteoglycans.

Nature, 2021; DOI: 10.1038/s41586-021-03818-3 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210826111704.htm

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